Download Can supplementation with vitamin E or C and omega-3 or

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Can supplementation with vitamin E or C and omega-3 or -6 fatty acids improve ...
Can supplementation with vitamin E or
C and omega-3 or -6 fatty acids
improve the outcome of schizophrenia?
Ali lahko vitaminom E ali C in omega-3 ali -6
maøœobne kisline izboljøajo izide zdravljenja
shizofrenije?
Marija Boøkoviå, Tomaæ Vovk
Abstract: Background: Schizophrenia is a major mental disorder associated with high morbidity and economic cost. It is important to develop
alternative or supplementary treatment strategies that could augment antipsychotic actions and reduce side effects. Increasing evidence indicate that oxidative damage is present in patients with schizophrenia. Oxidative mediated damage is suggested by an increase in lipid peroxidation products in cerebrospinal fluid and plasma, and a reduced concentration of membrane polyunsaturated fatty acids in neurons. Lipid peroxidation can be prevented by antioxidant supplementation and on the other hand the process of phospholipids regeneration can be increased
by supplementation with essentially fatty acids. Objective: To review available data on the clinical effects of vitamin E or C and omega-3 or -6
fatty acids for supplementary treatment of patients with schizophrenia. Main results: Trials on a limited number of subjects with an uncertain
quality of randomisation indicate that vitamin E protects against deterioration of tardive dyskinesia but there is no evidence that vitamin E supplementation improves symptoms of tardive dyskinesia. As concerns vitamin C, there is not enough data for evaluation. Until now, the results
show that oral supplementation with vitamin C restore ascorbic acid levels, reduce oxidative stress, and improve Brief Psychiatric Rating Scale
score. The results of supplementation therapy with polyunsaturated fatty acids remain inconclusive. Omega-3 fatty acids have the greatest
potential of all fatty acids to reduce movement disorder outcomes as expressed by the Abnormal Involuntary Syndrome Scale score. Combined
therapy with antioxidants and polyunsaturated fatty acids is the most promising approach to prevent oxidative damage and enable regeneration of phospholipids in neurons, but its potential has to be confirmed in future clinical studies. Conclusion: The use of antioxidants and omega3 polyunsaturated fatty acids in adjuvant treatment of schizophrenia still remains hypothetical and there is a need for large, well designed and
reported studies. Potentially it could be an effective, low cost, supplementary treatment with few side effects. Therefore, such therapy would be
a significant advance in schizophrenia.
Key words: schizophrenia, oxidative stress, vitamin E, vitamin C, omega-3 and -6 fatty acids
Povzetek: Uvod: Shizofrenija je pomembna duøevna bolezen povezana z velikim deleæem obolevnosti in ekonomskimi stroøki. Prav zato je
potrebno razviti alternativne ali adjuvantne terapije, ki bi sedanjo antipsihotiœno terapijo izboljøale predvsem pa omilile njene neæelene uœinke.
Øtevilni dokazi potrjujejo oksidativne poøkodbe pri bolnikih s shizofrenijo. To so poveœane koncentracije produktov lipidne peroksidacije v cerebrospinalni tekoœini in plazmi ter zniæane koncentracije polinenasiœenih maøœobnih kislin v membranah nevronov. Lipidno peroksidacijo lahko
prepreœimo s terapijo z antioksidanti, medtem ko lahko procese regeneracije fosfolipidov pospeøimo z uvedbo terapije z esencialnimi maøœobnimi kislinami. Namen: Pregled rezultatov kliniœnih øtudij, kjer so bolniki s shizofrenijo prejemali adjuvantno terapijo z vitamino E ali C in omega3 ali -6 maøœobnimi kislinami. Rezultati: Øtudije z majhnim øtevilom bolnikov s shizofrenijo in z dvomljivo randomizacijo so pokazale, da vitamin
E prepreœuje napredovanje tardivne diskinezije, vendar pa ne omogoœa tudi izboljøanje njenih simptomov. Øtudij z adjuvantno terapijo z vitaminom C je premalo. Dosedanji rezultati kaæejo, da peroralna aplikacija vitamina C poveœa zniæane koncentracije vitamina C, zmanjøa oksidativni stres in izboljøa psihiatriœno stanje ovrednoteno po kratki psihiatriœni ocenjevalni lestvici. Rezultati adjuvantne terapije s polinenasiœenimi
maøœobnimi kislinami ostajajo nejasni. Omega-3 maøœobne kisline so najbolj obetajoœe maøœobne kisline, ki lahko izboljøajo motnje gibanja
ocenjene z lestvico abnormalnih nehotnih gibov. Potencialno najuspeønejøo adjuvantno terapijo za prepreœevanje oksidativnih poøkodb in
regeneracijo fosfolipidov v neuronih predstavlja kombinacija maøœobnih kislin in antioksidantov, vendar je tudi to potrebno øe potrditi v kliniœnih
raziskavah. Zakljuœek: Uporaba antioksidantov in omega-3 polinenasiœenih maøœobnih kislin za adjuvantno zdravljenje shizofrenije ostaja øe
vedno na raziskovalni ravni, zato je potrebno izvesti velike, dobro naœrtovane in dokumentirane øtudije. Ta kombinacija adjuvantne terapije bi
lahko bila uspeøna, z malo neæelenimi uœinki in nizko ceno zato lahko predstavlja pomemben napredek pri zdravljenju shizofrenije.
Kljuœne besede: shizofrenija, oksidativen stres, vitamin E, vitamin C, omega-3 in -6 maøœobne kisline
Marija Boøkoviå, M. Pharm., Faculty of Pharmacy, The Chair of Biopharmaceutics and Pharmacokinetics, Aøkerœeva 7, 1000 Ljubljana, Slovenia
dr. Tomaæ Vovk, M. Pharm., Faculty of Pharmacy, The Chair of Biopharmaceutics and Pharmacokinetics, Aøkerœeva 7, 1000 Ljubljana, Slovenia
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Introduction
Schizophrenia is a major mental disorder associated with high
morbidity and economic cost. The illness has a poor outcome in spite
of the best currently available treatment. It is the most common cause
of chronic psychosis and affects approximately 1 % of the world's
population. Its cardinal signs include active psychosis, such as
delusions and hallucinations, the disturbance of logical thought
processes, and deterioration of social and occupational functions.
Two terms are commonly used to categorize the symptoms of
schizophrenia. Positive symptoms refer to new mental phenomena,
which unaffected people normally do not experience, such as
hallucinations and delusions. Negative symptoms refer to a loss of
normal mental functions leading for example to amotivation and social
withdrawal. More recently, impaired cognition has been identified as
a third domain of abnormality in schizophrenia (1). Schizophrenia is
associated with a broad range of neurodevelopmental, structural and
behavioral abnormalities that often progress with or without treatment.
Evidence indicates that such neurodevelopmental abnormalities may
result from defective genes and/or non-genetic factors such as prenatal and neonatal infections, birth complications, famines, maternal
malnutrition, drug and alcohol abuse, season of birth, sex, birth order
and life style (2, 3). According to the classical dopamine (DA)
hypothesis, schizophrenia is associated with increased dopaminergic
activity in the specific brain structures. Increased dopaminergic
activity is supported by increased number and sensitivity of
dopaminergic D2 receptors and overproduction or reduced
destruction of dopamine (4).
The scope of this article is to review major mechanisms of oxidative
stress development in patients with schizophrenia and in particular to
review potential therapeutic strategies using supplementation with
vitamin E and C and omega-3 and -6 polyunsaturated fatty acids to
prevent oxidative injuries and improve clinical outcome of
schizophrenia.
Oxidative stress
Increasing evidence indicates that oxidative damage exists in
schizophrenia. Although this may not be the main cause, oxidative
damage has been suggested to contribute to its pathophysiology and
may account for the deteriorating course and poor outcome in
schizophrenia (9, 10).
Under physiological conditions, dopamine (DA) which has a
dihydroquinone structure, is non-enzymatically oxidized by molecular
oxygen to form hydrogen peroxide (H2O2) and the corresponding oquinone. Subsequently, o-quinone undergoes an intramolecular
cyclization which is immediately followed by a cascade of oxidative
reactions resulting in the final formation of a black, insoluble polymeric
pigment known as neuromelanin. During the oxidation of dopamine
and its precursor L-DOPA, the superoxide radical (O2•-) and H2O2 can
be produced. For these compounds, the rate of oxidation is
accelerated by the presence of transition-metal ions such as iron and
copper. In the presence of such metals, in addition to O2•-, H2O2,
semiquinones, and quinones, the hydroxyl radical (OH•) is produced
during oxidation. The molecular mechanism generally accepted for
OH• production during DA autoxidation is the following:
Antipsychotics have been used to treat schizophrenia for over 50
years. Classical antipsychotic agents such as haloperidol,
fluphenazine, levomepromazine, promazine and others are potent
antagonists of dopamine receptors, mainly D2. Atypical
antipsychotics like clozapine, risperidone, olanzapine, quetiapine and
others have a higher affinity for other receptors, such as serotonin
receptors (5-HTA2). It also seems that they have therapeutic effects
against negative symptoms and cognitive deficits that are considered
to be difficult to treat (1).
Classical and atypical antipsychotics differ in their neurotransmitter
receptor affinity profiles but also in their efficacy and side effects in
patients with schizophrenia. Classical antipsychotics have
extrapyramidal side effects such as tardive dyskinesia which is a
movement disorder and is characterised by abnormal, repetitive and
involuntary movements. It has also been found that they increase
oxidative cellular stress more than atypical antipsychotics. According
to literature data, administration of classical antypsychotics induces
oxidative stress and provokes attenuation of antioxidant enzymes and
cell oxidative damage. Few authors have conducted experiments with
classical and atypical antipsychotics. They came to unique
conclusion, that after a classical antipsychotic administration
concentration of antioxidant enzymes is lower and concentration of
lipid peroxidation marker, malondialdehyde, is significantly higher.
Therefore, it has been proposed, that oxidative damage is one of the
mechanisms of classical antipsyhotics toxicity. Furthermore, it has
been suggested, that neuronal cell damage caused by reactive
species (RS) is a pathophysiological explanation for formation of
neuroleptic induced tardive dyskinesia. (5, 6, 7, 8).
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which involves an initial production of the O2•-, from which H2O2 is
formed, to finally give OH• through the Fenton reaction. Additionally,
this process involves the formation of o-quinone from the
corresponding semiquinone radical (11, 12, 13).
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Oxidative deamination of dopamine by monoamine oxidase (MAO)
can lead to formation of H2O2 and 3,4-dihydroxyphenylacetaldehyde.
The latter compound is then oxidized by aldehyde dehydrogenase to
give 3,4-dihydroxyphenylacetic acid, which subsequently is
methylated by catechol-O-methyltransferase to form homovanillic
acid (14, 15).
Therefore, both the autoxidation and the MAO-mediated metabolism
of DA involve the formation of H2O2, a compound that can easily be
reduced in the presence of ferrous ion to form, through the Fenton
reaction, the OH• radical, which is considered the most damaging
free radical for living cells. Important iron-containing proteins in the
brain include cytochromes, ferritin, aconitases, mitochondrial nonhaem-iron proteins, cytochromes P450 and the tyrosine and
tryptophan hydroxylase enzymes, which catalyse the first steps in the
synthesis of dopamine and serotonin. In the dopaminergic neurons
neuromelanine is also present, which has a reported ability to
accumulate iron and consequently may act by promoting the Fenton
reaction (16, 17, 18). As iron content in the brain is high, dopamine
autoxidation is accelerated and therefore probably responsible for the
majority of ROS production (12).
Schizophrenia is characterised by increased amounts of DA. Both
untreated and treated patients have an increased possibility of
oxidative cell damage, but in patients treated with classical
antipsychotics oxidative damage is more expressed. Since classical
antipsyhotics block DA receptors, DA remains unbound in the
synapses. Therefore, large amounts of DA are available for processes
of biotransformation. Consequently, it has been proposed that
haloperidol-induced oxidative stress arises from the increased
production of hydrogen peroxide caused by the catecholamine
metabolism with monoamine oxidase and autooxidation of dopamine.
Again, we can speculate that iron accelerates dopamine
autooxidation which therefore mainly contributes to RS production.
Another possible source of reactive species in haloperidol toxicity is
the electron transport chain of mitochondria which is blocked by
haloperidol (17).
Consequences of oxidative stress
Oxidative stress is defined as a disturbance in the prooxidantantioxidant balance in favour of the former, leading to potential
damage. This means that diminished antioxidants and/or increased
production of reactive species will result in oxidative damage.
Oxidative damage is the biomolecular damage caused by attack of
reactive species upon the constituents of living organisms (11).
Reactive species can damage lipids, proteins, enzymes,
carbohydrates and DNA in cells, resulting in membrane damage,
fragmentation or random cross-linking of molecules like DNA,
enzymes and structural proteins, and even lead to cell death induced
by DNA fragmentation and lipid peroxidation. In the neuronal cells
and glia the consequences are increased lipid peroxidation, oxidative
damage to DNA, damage to proteins and induction of apoptosis and
necrosis (11).
Since many studies have confirmed increased lipid peroxidation in
patients with schizophrenia, lipids probably represent the main target
among cell macromolecules for oxidative damage. Phospholipids,
cholesterols, saturated fatty acids and monounsaturated fatty acids
can be synthesized de novo within the human body. Because
mammals cannot introduce a double bond beyond the delta-9
position in the fatty acid chain, omega-6 and omega-3 must be
regained through the diet. Polyunsaturated fatty acids are major
components of membrane phospholipids and are highly susceptible
to reaction with free radicals, with the resultant formation of peroxy
radicals and lipid peroxides. These products in the cell membrane
result in an unstable membrane structure, and altered membrane
fluidity and permeability. Many investigators reported decreased
levels of essential fatty acids (EFA) in both the peripheral and central
membranes of patients with schizophrenia (5, 19).
For a long time, altered membrane phospholipid metabolism has
been considered as the pathophysiological basis of schizophrenia.
Several studies have reported variable changes in the levels of
membrane phospholipids in erythrocytes and cultured skin
fibroblasts. Alternation of the phospholipid metabolism is also
reflected in the decrease of phosphomonoesters, indicating reduced
synthesis, and the increase of phosphodiesters, indicating increased
breakdown. Recent attention has been focused on abnormal essential
polyunsaturated fatty acid metabolism. This seems quite appropriate
since the dietary availability of essential fatty acids and their utilization
in synthesis of phospholipids determines the quantity and quality of
membrane phospholipids, particularly in the brain, since brain
phospholipids are highly enriched in essential fatty acids, primarily
arachidonic acid, an omega-6 series, and docosahexaenoic acid, an
omega-3 series. Reduced membrane levels of EFA have been
consistently reported in red blood cells, brain and skin fibroblasts
from chronically medicated patients with schizophrenia, as well as
drug naive patients (20).
Therapeutic strategies for the
prevention of oxidative damage
ROS damage can be ameliorated by at least two mechanisms;
inactivation of ROS by dietary antioxidants (e.g., vitamin C, vitamin E),
and replacement of lost membrane EFA by dietary supplementation
with essential fatty acids.
Vitamin E is a lipid soluble antioxidant with the potential to prevent
oxidative damage. However, vitamin E cannot prevent oxidative
damage to cytosolic proteins, mitochondria, and nuclei, where most
of the ROS are generated. Therefore, it may be important to use
vitamin E in combination with vitamin C, a water soluble antioxidant.
The supplementary use of vitamin C in schizophrenia requires caution
since a high dietary intake of iron will result in vitamin C having a
prooxidant rather than an antioxidant action. The addition of essential
polyunsaturated fatty acids could promote recovery of previously
damaged membrane structures. It is proposed that ongoing oxidative
cell damage must be stopped and that structural membrane damage
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must be reversed. Since antioxidants alone may stop ongoing
oxidative damage and EFA have the potential to restore the cellular
structure their combined use may be necessary for optimal treatment
of oxidative cell damage (21).
The results of studies available in the literature in which these
therapeutic strategies were used are presented in Table 1 and Table 2.
Vitamin E and vitamin C are well known antioxidants that are
postulated to protect against damage to biological membranes by
their ability to scavenge free radicals. Accordingly, several studies
have examined the efficacy of vitamin E or vitamin C in the treatment
of schizophrenia (Table 1).
According to statistical analysis of the results of ten clinical studies,
there is no evidence that vitamin E reduces the symptoms of tardive
dyskinesia. The studies were designed as controlled trials involving
patients with antipsychotic-induced tardive dyskinesia and
schizophrenia, or other chronic mental illness, who were randomly
allocated to either vitamin E or to a placebo or no intervention. The
overall results for clinically relevant improvement showed no benefit of
vitamin E against placebo (6 trials, 256 people). Small scale trials with
an uncertain quality of randomisation indicate that vitamin E protects
against deterioration of tardive dyskinesia but there is no evidence
that vitamin E improves symptoms of this disease (22).
As concerns vitamin C, there is a lack of available data. In the first
study that we identified the aim was to examine the effect of peroral
application of vitamin C with atypical antipsychotics on serum
malondialdehyde, plasma ascorbic acid levels, and Brief Psychiatric
Rating Scale (BPRS) score in patients with schizophrenia. The
patients with schizophrenia had increased serum malondialdehyde
levels and decreased plasma ascorbic acid levels, which proves
increased oxidative stress. These levels were significantly reversed
after treatment with vitamin C along with atypical antipsychotics
compared to placebo with atypical antipsychotics. BPRS scores
improved significantly with addition of vitamin C as compared to
Table 1: Effect of supplemental treatment (vitamin E and C) on patients with schizophrenia in double blind randomised studies. Reports for
vitamin E were included according to data from the Cochrane library data base (22).
Preglednica 1: Uœinek adjuvantne terapije (vitamin E in C) pri bolnikih s shizofrenijo v dvojno slepih randomiziranih øtudijah. Podatki za
adjuvantno terapijo z vitaminom E so v skladu s podatkovno bazo “Cochrane library data base” (22).
Vitamin E studies
Study duration,
number of patients
Intervention
Outcome
Adler 1993
36 weeks, N=40
Vitamin E 1600 IU/day
Significant reduction of AIMS score in favour of
vitamin E
Adler 1999
1 year, N=158
Vitamin E 1600 IU/day
No significant reduction of AIMS and BPRS
Akhtar 1993
4 weeks, N=32
Vitamin E 1200 IU/day
Significant reduction of TDRS
Dabiri 1994
12 weeks, N=12
Vitamin E 1200 IU/day
Significant reduction of AIMS
Egan 1992
6 weeks, N=21
Vitamin E 1600 IU/day
No significant reduction of AIMS
Elkashef 1990
4 weeks, N=10
Vitamin E 1200 IU/day
Significant reduction of AIMS
Lam 1994
6 weeks, N=16
Vitamin E 1200 IU/day
No significant reduction of AIMS
Lohr 1996
8 weeks, N=55
Vitamin E 1600 IU/day
Significant reduction of AIMS and not of BPRS
Sajjad 1998
7 months, N=20
Vitamin E 600 IU/day
Significant reduction of AIMS score
Schmidt 1991
2 weeks, N=23
Vitamin E 1200 IU/day
No significant reduction of AIMS
Vitamin C studies
Study duration,
number of patients
Intervention
Outcome
Nikolaus 2002 * (23)
2 years , N=6
Vitamin C 200 mg/day
and vitamin E 1.8 mg/day
Significant reduction in dyskinetic movements total
score
Vitamin C 500 mg/day
Significant reduction in MDA and BPRS
Dakhale 2005 (24)
8 weeks , N=40
* prospective open study
(AIMS- Abnormal Involuntary Movement Syndrome Scale, BPRS- Brief Psychiatric Rating Scale, PANSS- Positive and Negative Syndrome Scale, M-ADRSMontgomery-Asberg Depression Rating Scale, S-ARS- Simpson-Angus Rating Scale, TDRS- Tardive Dyskinesia Rating Scale, CGI- Clinical Global Impression Scale,
QOL- Henrich’s Quality of Life scale, EPA- Eicosapentaenoic acid, E-EPA- Ethyl eicosapentaenoic acid, DHA- Docosahexaenoic acid, MDA- Malondialdehyde).
(AIMS- Lestvica abnormalnih nehotnih gibov, BPRS- Kratka psihiatriœna ocenjevalna lestvica, PANSS- Lestvica za ocenjevanje pozitivnega in negativnega sindroma, M-ADRS- Montogmery-Asberg ocenjevalna lestvica depresije, S-ARS- Simpson-Angus ocenjevalna lestvica, TDRS- Ocenjevalna lestvica tardivne diskinezije,
CGI- Lestvica sploønega kliniœnega vtiska, QOL- Henrihova lestvica ocenjevanja kakovosti æivljenja, EPA- Eikozapentaenojska kislina, E-EPA- Etil eikozapentaenojska kislina, DHA- Dokozaheksaenojska kislina, MDA- Malondialdehid).
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Table 2: Effect of supplemental treatment (polyunsaturated fatty acids or a combination of antioxidants and polyunsaturated fatty acids) on
patients with schizophrenia in double blind randomised studies. Reports for fatty acid supplemental therapy were included
according to data from the Cochrane library data base (25).
Preglednica 2: Uœinek adjuvantne terapije (polinenasiœene maøœobne kisline ali kombinacija antioksidanta in polinenasiœenih maøœobnih
kislin) pri bolnikih s shizofrenijo v dvojno slepih randomiziranih øtudijah. Podatki za adjuvantno terapijo s polinenasiœenimi
maøœobnimi kislinami so v skladu s podatkovno bazo “Cochrane library data base” (25).
Fatty acids studies
Method
Intervention
Outcome
Emsley 2002
12 weeks, N=40
E-EPA 3g/day
Significant reduction in PANSS scores
Fenton 2001
16 weeks, N=90
E-EPA 500 mg/day
and vitamin E
No significant change in PANSS, M-ADRS, AIMS,
S-ARS, CGI
Peet 2001
12 weeks, N=55
EPA 2g, DHA 2g
Comparative study
Significant reduction in PANSS scores.
EPA is superior to DHA
Peet 2002
12 weeks, N=55
EPA 1g/day, EPA 2g/day,
EPA 3g/day, EPA 4g/day.
Comparative study
Significant reduction in PANSS scores,
the bigest for those who had EPA 2g/day
Wolkin 1986
12 weeks, N=55
Gama-linoleic acid 600 mg/day
No significant reduction in AIMS
Mellor 1995
6 weeks, N=20
EPA, 10 g MaxEPA fish oil
Significant reduction in PANSS scores and AIMS
Vitamins E and C
and fatty acids
Method
Intervention
Outcome
EPA/DHA 180:120 mg
Vitamin E/C 400 IU/ 500mg
Significant reduction of PANSS and BPRS
and increase of QOL
Arvindakshan 2003 (21) 4 months, N=33*
* prospective open study
(AIMS- Abnormal Involuntary Movement Syndrome Scale, BPRS- Brief Psychiatric Rating Scale, PANSS- Positive and Negative Syndrome Scale,
M-ADRS- Montgomery-Asberg Depression Rating Scale, S-ARS- Simpson-Angus Rating Scale, TDRS- Tardive Dyskinesia Rating Scale, CGI- Clinical Global
Impression scale, QOL- Henrich’s Quality of Life scale, EPA- Eicosapentaenoic acid, E-EPA- Ethyl eicosapentaenoic acid, DHA- Docosahexaenoic acid,
MDA- Malondyaldehide).
(AIMS- Lestvica abnormalnih nehotnih gibov, BPRS- Kratka psihiatriœna ocenjevalna lestvica, PANSS- Lestvica za ocenjevanje pozitivnega in negativnega sindroma, M-ADRS- Montogmery-Asberg ocenjevalna lestvica depresije, S-ARS- Simpson-Angus ocenjevalna lestvica, TDRS- Ocenjevalna lestvica tardivne diskinezije,
CGI- Lestvica sploønega kliniœnega vtiska, QOL- Henrihova lestvica ocenjevanja kakovosti æivljenja, EPA- Eikozapentaenojska kislina,
E-EPA- Etil eikozapentaenojska kislina, DHA- Dokozaheksaenojska kislina, MDA- Malondialdehid).
placebo after 8 weeks of treatment. It can be concluded that oral
supplementation of vitamin C with atypical antipsychotics restore
ascorbic acid levels, reduces oxidative stress, and improves the
BPRS score (24). In the second study when a combination of both
antioxidants (vitamin E and vitamin C) was used, the results showed
that the dyskinetic movements total score was significantly reduced.
Results of the vitamin combination are promising and further studies
on this combination therapy are suggested (23).
It is difficult to make a direct comparison between vitamin C and
vitamin E effects in schizophrenia according to available clinical
studies. Class of antipsychotic treatment, duration of disease and
duration of treatment should be standardised. Moreover, there are
only two vitamin C studies, and one of them is conducted on six
patients. Furthermore, to compare antioxidant effects, we would need
to evaluate markers of oxidative stress and oxidative damage.
In the light of presented data, additional randomised clinical study
with vitamin C, vitamin E and placebo group would be needed.
Patients should be treated with same group of antipsychotics
(suggested is typical antipsychotic) and markers of oxidative stress
and oxidative damage should be quantified.
To review the effects of EFA supplementation of antipsychotic
treatment for schizophrenia-like illnesses we present the most recent
data (Table 2). When the use of omega-3 is compared to placebo,
small scale short trials suggest that the need for antipsychotics
appears to be reduced in patients treated with omega-3
supplementation due to improvement in their mental state. There are
limited data comparing the effect of omega-6 to placebo. For
movement disorder outcome, only one small study does not show any
difference for the average short-term endpoint AIMS score. When
different omega 3 fatty acids (E-EPA, EPA, DHA) are compared there
is no clear difference in the outcome of Positive and Negative
Syndrome Scale (PANSS) scores. Comparison of different dose levels
of omega-3 with placebo revealed no difference in the measure of
global and mental state. Despite all these data, there is currently no
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clear evidence of the effectiveness of fatty acids. Clinicians should
prescribe an omega-3 preparation as part of a well-designed
randomised trial. It is important that researchers record and release
all clinically relevant data. There are still too few data on the role of
essential fatty acid supplementation in the treatment of patients with
schizophrenia. The value of polyunsaturated fatty acids for treating
schizophrenia is not yet confirmed. The intriguing theory behind their
use and even the possibility of a clinical effect could create a whole
new path of research. Support of a substantial study would seem
warranted (25).
Despite the fact that combined therapy with antioxidants and EFA is
potentially more effective than monotherapy in patients with
schizophrenia, we have identified only one study with an appropriate
design (21). In this study morning and evening oral supplementation
with antioxidants (vitamin E/C, 400 IU: 500 mg) and a mixture of
EPA/DHA (180:120 mg) was used in treatment of patients with
schizophrenia (N = 33) for 4 months. Post-treatment levels of red
blood cell EFA were significantly higher than pre-treatment levels, as
well as the levels in healthy controls, without any significant increase
in plasma peroxides. Additionally, there was a significant reduction in
psychopathology based on a reduction in individual total scores on
the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative
Syndrome Scale (PANSS) and an increase in Henrich’s Quality of Life
(QoL) Scale. General psychopathology-PANSS is part of the whole
PANSS and its mention does not mean much if the changes on the
part of positive and negative symptoms are not quoted. (21).
Conclusion
The use of antioxidants and omega-3 polyunsaturated fatty acids in
the treatment of schizophrenia still remains to be established and
there is a need for large well designed, conducted and reported
studies. Future studies need to be done in placebo-controlled trials
with a larger number of patients, both chronic as well as drug naive,
and for a longer duration of treatment while the dietary intake is
monitored. Previous studies indicated several critical issues that must
be considered in designing and carrying out future studies. The age
of the patients and years of the illness may be an important issue
since the age has been associated with the potentially reduced
antioxidant defence, and the years of illness and treatment,
particularly with classical antipsychotics such as haloperidol, may
lead to state of membrane pathology which is difficult to repair.
Despite the fact that some of the studies gave positive results, there
is currently no reason for clinicians to either encourage or discourage
the use of polyunsaturated fatty acids. If a person with schizophrenia
wishes to use EFA supplementation then an omega-3 preparation
should be the preferred option. Finally, combined therapy with
antioxidants and EFA has an improved potential in preventing
oxidative damage and repairing already existing damage, but this has
to be confirmed in future clinical studies.
Polyunsaturated fatty acids (omega-3) together with antioxidant
vitamins could be an effective, low cost, supplemental treatment with
few side effects. Therefore, such therapy would be a significant
advance in the treatment of schizophrenia.
172 farm vestn 2008; 59
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